LY6D identifies persistent stem-like cells driving pancreatic tumourigenesis

Area of Science:

• Oncology
• Cell Biology
• Cancer Genomics

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is aggressive and heterogeneous, with early pre-malignant cell states driving progression.
• The specific transcriptional, metabolic, and functional characteristics of these early PDAC-initiating cells remain unclear.

Purpose of the Study:

• To identify and functionally characterize critical pre-malignant cell states in PDAC.
• To discover novel biomarkers and therapeutic targets for early PDAC intervention.

Main Methods:

• Analysis of single-cell RNA sequencing (scRNA-seq) data from PDAC models.
• Genetic perturbations in KrasG12D-driven models to assess functional roles.
• Proximity proteomics, epigenetic profiling, metabolic assays, and validation in human PDAC cohorts.

Main Results:

• LY6D was identified as a marker for an early, persistent gastric-like cell state with stemness properties.
• This LY6D-positive population relies on oxidative phosphorylation (OXPHOS) and influences tumor progression.
• LY6D overexpression enhanced tumor potential, while its ablation delayed tumorigenesis; high LY6D expression is a poor prognostic marker in human PDAC.

Conclusions:

• The LY6D-positive gastric-like cell state is a key driver linking PDAC heterogeneity to tumor initiation and progression.
• LY6D serves as a potential pan-stage therapeutic target and a biomarker for early PDAC detection and treatment.